Yasuaki Yamada

Deletions of p15 and/or p16 genes as a poor-prognosis factor in adult T-cell leukemia.

PURPOSEnTo determine the frequency of the deletions of p15/p16 genes in adult T-cell leukemia (ATL) cells and to evaluate their value in the diagnosis of clinical subtypes of ATL patients and the prediction of their clinical outcome.nnnMATERIALS AND METHODSnPeripheral-blood samples from 114 patients with ATL were examined by Southern blot analysis. In five chronic-type patients who showed disease progression to acute type, serial samples also were examined.nnnRESULTSnAmong 114 patients, 28 (24.6%) showed the deletions of p15 and/or p16 genes. The results were well correlated with the clinical subtypes. Patients with deleted p15 and/or p16 genes had significantly shorter survival times than the patients in whom both genes were preserved (P < .0001). A similar decline in survival time was observed in the analyses within the same subtypes. In multivariate analysis using the Cox proportional hazard model, the deletions of p15 and/or p16 genes emerged as an independent prognostic indicator. Moreover, three of the five chronic-type patients who progressed to acute type lost the p16 gene alone or both the p15 and p16 genes at their exacerbation phase.nnnCONCLUSIONnThe results suggest the following: (1) that the deletions of p15 and/or p16 genes play a key role in the progression of ATL; and (2) that these deletions are reliable prognostic factors that predict shortened survival times.

Poor outcome of autologous stem cell transplantation for adult T cell leukemia/lymphoma: a case report and review of the literature

A limited number of patients with adult T cell leukemia/lymphoma (ATL) who received autologous stem cell transplantation (ASCT) have been reported. We report here a case of fatal systemic Candida krusei infection in a female patient with ATL undergoing ASCT. All of the eight patients (including seven patients in the literature) with ATL who received ASCT developed relapse of ATL or death due to ASCT complication, irrespective of subtype or remission state of ATL, source or selection of SCT or conditioning regimen. At present, ASCT appears to provide little benefit for ATL in contrast to that for other types of aggressive non-Hodgkin’s lymphoma.

The methylthioadenosine phosphorylase gene is frequently co-deleted with the p16INK4a gene in acute type adult T-cell leukemia.

Adult T‐cell leukemia (ATL) is a retrovirus‐associated leukemia with poor prognosis and often has deletions of the p16INK4a and p15INK4b genes on chromosome 9p21. The gene for methylthioadenosine phosphorylase (MTAP), a purine and methionine metabolic enzyme, resides approximately 100 Kb telomeric to the p16INK4a gene and is frequently co‐deleted with the tumor suppressor gene in a variety of cancers. This enzyme deficiency can be exploited for selective chemotherapy with de novo purine synthesis inhibitors and/or methionine depletion. To determine whether ATL can be a candidate for selective chemotherapy based on genetic alterations on chromosome 9p21, we analyzed the MTAP gene in 41 samples from ATL patients (27 acute type and 14 chronic type ATL) and 3 cell lines established from ATL patients. Five samples from the acute type had deletions of the MTAP gene (4 total deletions and 1 partial deletion of exons 6–8). The MTAP gene was always co‐deleted with p16INK4a. No deletion of the MTAP gene was detected in samples from the chronic type. Of 3 cell lines, 2 showed partial deletions of exons 5–8 of the MTAP gene, and 1 lost all exons. The p16INK4a gene was deleted in all cell lines. In conclusion, deletions of the MTAP gene were found in 5 of 27 acute type ATL samples. Acute type ATL with MTAP deficiency can be a good candidate for selective chemotherapy by depleting purines and/or methionine. Int. J. Cancer 75:51–56, 1998.© 1998 Wiley‐Liss, Inc.

Circulating interleukin‐6 levels are elevated in adult T‐cell leukaemia/lymphoma patients and correlate with adverse clinical features and survival

We measured the circulating levels of interleukin (IL)‐6 in adult T‐cell leukaemia/lymphoma (ATL) patients using an enzyme‐linked immunosorbent assay. The IL‐6 levels in 59 ATL patients (median 8.2u2003pg/ml; range <u20031.0 to 185.7u2003pg/ml) were significantly higher than in 30 healthy controls (median <u20031.0u2003pg/ml; range <u20031.0 to 3.5u2003pg/ml) (Pu2003<u20030.0001) or 32 human T‐lymphotropic virus type‐I (HTLV‐I) carriers (median 4.2u2003pg/ml; range u2003<u20031.0 to 13.3u2003pg/ml) (Pu2003=u20030.002). Among the ATL patients, the IL‐6 levels in the acute‐ or lymphoma‐type patients were significantly higher than those in the chronic‐type patients (Pu2003<u20030.0001). The IL‐6 levels were also higher in the patients with B symptoms than in those without B symptoms (Pu2003=u20030.039), and were significantly correlated with increased serum lactate dehydrogenase (LDH) (Pu2003=u20030.0004) and C‐reactive protein (CRP) (Pu2003<u20030.0001) and decreased serum albumin (Pu2003=u20030.0003) values. The patients with elevated IL‐6 levels had inferior overall survival periods compared to those with normal IL‐6 levels (Pu2003=u20030.025). ATL is a single disease entity, although its clinical features are quite diverse; the increased production of cytokines may cause the diversity of clinical features. The results of our study indicate that IL‐6 is one such cytokine.

Quantitative characterization and potential function of membrane Fas/APO‐1 (CD95) receptors on leukaemic cells from chronic B and T lymphoid leukaemias

The expression and function of the Fas‐receptor (Fas‐R) were examined in chronic lymphocytic leukaemia (CLL), hairy cell leukaemia‐variant (HCL‐v) and adult T‐cell leukaemia (ATL). The expression of Fas‐R in freshly isolated leukaemic cells was qualitatively and quantitatively different between each disease; faint in B‐CLL, moderate in HCL‐v and strong in ATL. Both full‐length and alternatively spliced truncated forms of Fas mRNA were detected even in CLL B cells with faint to negative Fas‐R, and Fas mRNA was also shown to be capable of increasing in vitro expression, i.e. the message was functional. In contrast, Fas‐R expression on ATL cells was heterogenous and usually intense with a mean density approximately 3‐fold higher than that of normal T cells. Fas‐R was confirmed to have the potential function for anti‐Fas monoclonal antibody‐mediated cell death in vitro in Fas‐R+ ATL cells. The expression level of Fas‐R on the cells was higher in chronic than acute ATL (10360 v 6260 antibody‐binding capacity per cell, mFasABC; Pu2003<u20030.05) and was inversely correlated with serum LDH activity, suggesting that the strong Fas‐R accounts for the slow progression of chronic ATL and the negative Fas‐R protects from Fas‐mediated cell death. These results show that Fas‐R expression on leukaemic cells is valuable in their characterization and perhaps their function, and may contribute to the progression and immune evasion of malignant clones.

Retinoic acids induce growth inhibition and apoptosis in adult T-cell leukemia (ATL) cell lines

Adult T-cell leukemia (ATL) is a peripheral T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). Despite the administration of combined intensive chemotherapy, the reported survival time of patients with acute and lymphoma types of ATL is less than 10 months. We therefore examine the effects of all-trans-retinoic acid (ATRA), 9-cis-RA and 13-cis-RA and tried to elucidate the mechanisms of inducing growth inhibition and apoptosis by these RAs using four ATL cell lines established in our laboratory. All the investigated RAs inhibited cell growth and the cells were arrested at the G1 phase. Apoptosis was induced in three out of four cell lines. Among the growth regulatory proteins examined, the level of p21Waf1/Cip1 protein was found to increase after RA treatment, thus resulting in pRb hypophosphorylation which also induced the arrest of the cells at the G1 phase. In addition, the p53 level decreased at the same time. Fas-FasL system and the downregulation of CD25 (IL-2R/alpha) expression did not seem to be involved. Based on these findings, the ability of RAs to induce a remission of ATL is thus strongly suggested.

Diversity of leukaemic cell morphology in ATL correlates with prognostic factors, aberrant immunophenotype and defective HTLV-1 genotype

To investigate the diversity of morphology in adult T‐cell leukaemia/lymphoma (ATL) and its possible association with the pathophysiology of ATL, we selected 36 acute cases and 14 chronic cases phenotypically confirmed to have >90% ATL cells in peripheral blood mononuclear cells. Prototype ATL cells were observed in all cases, although the percentage of all lymphoid cells varied considerably (48.9u2003±u200323.8 in acute type, 29.6u2003±u200318.9 in chronic type; Pu2003=u20030.015). Chronic lymphocytic leukaemia (CLL)‐like morphology with round nuclei was more frequent in chronic type than in acute type (52.0u2003±u200324.9% v 16.6u2003±u200313.1%; Pu2003<u20030.0001). Unusual morphology (UM; lymphoblastic, vacuolated, granular pleomorphic or large cells) was more frequent in acute type than in chronic type (20.1u2003±u200318.7% v 2.7u2003±u20033.2%; Pu2003<u20030.0001). Furthermore, there were significant negative and positive correlations of % CLL‐like cells and % UM cells respectively, with serum LDH level, hypercalcaemia, performance status, and total number of involved lesions. Cases with aberrant immunophenotype (nu2003=u20036) or defective HTLV‐1 integration (nu2003=u200322) showed lower % CLL‐like cells and higher % UM cells than other cases, respectively. Cases with >50% CLL‐like cells (nu2003=u20037; all chronic type) were younger (53.1u2003±u200312.2 v 66.9u2003±u200310.6 years; Pu2003=u20030.038) and showed longer acute‐crisis free survival (mean: 16.7 v 3.0 years; Pu2003=u20030.012) than chronic cases with <50% CLL‐like cells. These results suggest that diversity in genotype, phenotype, morphology and behaviour of ATL are closely associated, and that CLL‐like morphology is a good prognostic factor for chronic type.

Soluble and membrane isoforms of Fas/CD95 in fresh adult T-cell leukemia (ATL) cells and ATL-cell lines.

Fas, also designated as Apo‐1 and CD95, is a cell membrane receptor (mFas) involved in apoptotic cell death. A soluble form (sFas) lacking the transmembrane domain due to alternative splicing has been isolated. Abnormal expression of sFas and mFas is likely to be involved in lymphoproliferative disorders and auto‐immune diseases. Adult T‐cell leukemia (ATL) caused by human T‐cell‐leukemia virus type‐1 (HTLV‐1) is well known to be a T‐cell neoplasm with strong mFas expression, suggesting a role of Fas in the pathology of the disease. We examined protein and mRNA expression of the 2 isoforms of Fas in fresh ATL cells and ATL cell lines. In general, mFas was strongly expressed in ATL cells, and sFas levels in sera were high, especially in malignant ATL. However, expression of the isoforms in some cases of ATL varied; there was no mFas expression on the cell surface and sFas levels were high in serum. In contrast, all ATL cell lines examined showed strong mFas expression and scarce production of sFas in the supernatant, corresponding to strong expression of full‐length Fas mRNA and weak to negative expression of alternatively spliced mRNA lacking the transmembrane domain. Our findings indicate that the mode of expression of Fas isoforms in ATL cells is not always homogenous and that Fas may play a role in the malignant behavior and oncogenesis of ATL. Int. J. Cancer 72:128–132, 1997.

Frequent Hepatic Involvement in Adult T Cell Leukemia: Comparison with non-Hodgkin's Lymphoma

We examined 111 patients with acute type- or lymphoma type-adult T-cell leukemia (ATL) and compared them with 106 patients with non-Hodgkins lymphoma (NHL). In addition to skin involvement and hypercalcemia which are already known to be frequent in ATL, ATL patients showed an higher incidence of hepatic involvement. There was more frequent palpable hepatomegaly, higher total bilirubin, GOT, GPT, lactate dehydrogenase (LDH), and alkaline phosphatase values in ATL than in NHL patients (p < 0.0001). Among 36 autopsied liver samples, invasion of ATL cells was confirmed in 22 cases. ATL patients with impaired hepatic function showed shorter survival times than patients without hepatic dysfunction. Moreover, ATL patients showed a worse performance status (PS), a higher incidence of lytic bone lesions, lower total protein (TP) and serum albumin levels than NHL patients. This invasive characters of ATL cells and consequent impaired general condition seemed to be factors affecting the poor prognosis recorded in ATL.

Vascular endothelial growth factor at high plasma levels is associated with extranodal involvement in adult T cell leukemia patients

Vascular endothelial growth factor at high plasma levels is associated with extranodal involvement in adult T cell leukemia patients